Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent

ABSTRACT

An oral pharmaceutical dosage form comprising a proton pump inhibitor and one or more prokinetic agents in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer. The fixed formulation is in the form of multilayered tablets, capsules or multiple unit tableted dosage forms. The multiple unit dosage forms are most preferred. The new fixed formulation is especially useful in the treatment of disorders associated with gastro oesophageal reflux diseases.

This application is a 371 of PCT/SE96/01736, filed Dec. 20, 1996.

FIELD OF THE INVENTION

The present invention is related to new oral pharmaceutical preparationsespecially for use in the prevention and treatment of disordersassociated with gastro oesophageal reflux. The present preparationscomprise a gastric acid suppressing agent, such as a proton pumpinhibitor, in combination with one or more prokinetic agents in a newfixed unit dosage form, especially a tablet. Furthermore, the presentinvention refers to a method for the manufacture of such preparationsand the use of such preparations in medicine, especially in thetreatment of gastro oesophageal reflux diseases and othergastrointestinal disorders.

BACKGROUND OF THE INVENTION

Gastro oesophageal reflux disease (GORD) is among the most commondisorders seen by gastroenterologists and general practicians. The widediversity of symptoms and disease severity produced by acid reflux hasled to the need for more individualized treatment strategies.Therapeutic agents effective in the treatment of GORD include gastricacid suppressing agents, such as H₂ receptor antagonists, proton pumpinhibitors, other agents of interest are antacids/alginates andprokinetic agents. These agents can be distinguished by their mechanismsof action, safety profile, pharmacokinetics and indications.

Antacids and alginates are still widely used. They have a short durationof action but are seen as inexpensive and safe. They do not provide alayterm symptom resolution of GORD.

H₂ receptor antagonists are widely prescribed for GORD. Their highercost has been compensated by the clinical results obtained both in termsof symptom relief and healing. These advantages have been related totheir mode of action, which offered more potent and longer duration ofeffect on gastric acidity.

Proton pump inhibitors, such as omeprazole, are rapidly taking sharefrom H₂ receptor antagonists, particularly in reflux oesophagitis.Omeprazole is known to offer significant gain over H₂ receptorantagonists in terms of symptom resolution, healing and prevention ofrelapse for reflux oesophagitis.

Prokinetic agents of the first generation, e.g. bethanecol, stimulatescholinergic receptors, and of the second generation, e.g. domperidoneand metoclopramide, blocks effects of endogenous dopamine in the gut.The results of double-blind placebo controlled trials in GORD patientshave been conflicting. The action of the third generation of prokineticagents, such as substituted benzamides, e.g. cisapride and mosapridederives primarily, but not exclusively, from facilitating acetylcholinerelease from neurones of the myenteric plexus via stimulation of 5-HT4receptors. The efficacy of orally administered benzamides, such ascisapride, in patients with GORD and reflux oesophagitis has beenstudied and a superior effect in alleviating gastro-oesophageal symptomsand healing low grade oesophagitis (non circumferential erosion) hasbeen shown in most studies.

Patients with severe symptoms, severe mucosal damage or both are almostalways treated with proton pump inhibitors for profound and long-termcontrol of gastric acid secretion. Patients with mild symptoms andlimited mucosal damage respond best to H2-receptor antagonist,prokinetic agents or proton pump inhibitors.

A combination therapy of a prokinetic agent and a gastric acid loweringcompound is rational and was shown more effective than mono therapyapart from full dose of proton pump inhibitors. Administration ofcisapride and ranitidine was shown to further lower the exposure of theoesophagus to acid(s) (Inauen W et al. Gut 1993; 34: 1025-1031). Such atherapy was also shown to improve healing rates (de Boer WA et al.Aliment Pharmacol Ther 1994; 8: 147-157). WO 95/01803 describes apharmaceutical composition of famitidine, cisapride and optionallysimethicone in the treatment of gastrointestinal distress.

Maintenance therapy is often necessary to prevent recurrent symptoms andoesophagitis. Recently a combination therapy combining anacid-suppressing medication with a prokinetic (cisapride) was shown alsovery effective. Further, Vyneri et al (N. Engl. J Med 1995; 333:1106-1110) found that omeprazole alone or in combination with cisapridewas more effective than ranitidine alone or cisapride alone and thatomeprazole combined with cisapride was more effective than ranitidineplus cisapride. Such combination therapies might be considered forpatients whose predominant symptom is regurgitation; those whosesymptoms occur mainly at night; those with respiratory problems such asposterior laryngitis, asthma, chronic bronchitis, or recurrentaspiration; those with cough and hoarseness related to reflux disease.

A combination therapy comprising an acid suppressing agent and aprokinetic agent is attractive, rational and effective. An acidsuppressing agent plus a prokinetic agent could be an alternative toeach of them separately in case of failure. However, because of thelarge number of therapeutical tablets/pills that must be taken each dayin such a therapy, the compliance of such a treatment may be a problem.It is well known that patient compliance is a main factor in receivinggood results in medical treatments. Administration of two, three or evenmore different tablets to the patient is not convenient or satisfactoryto achieve the most optimal results. The present invention now providesnew oral dosage forms comprising two or more different active substancescombined in one fixed unit dosage form, preferably a tablet.

It is well known that some of the gastric acid suppressing agents, suchas proton pump inhibitors are susceptible to degradation/transformationin acid reacting and neutral media. In respect of the stabilityproperties, it is obvious that the one of the active substances being anacid susceptible proton pump inhibitor must be protected from contactwith acidic gastric juice by an enteric coating layer. There aredifferent enteric coating layered preparations of proton pump inhibitorsdescribed in the prior art, see for example U.S. Pat No. 4,786,505 (ABHassle) describing a preparation comprising omeprazole.

There are problems to produce a fixed unit dosage form comprising arather high amount of active substance. Different active substances withdiffering physical properties in the same preparation give furtherproblems. Preparation of a multiple unit tableted dosage form encountersspecific problems when enteric coating layered pellets containing acidsusceptible proton pump inhibitors as active substance are compressedinto tablets. If the enteric coating layer does not withstand thecompression of the pellets into a tablet the susceptible activesubstance will be destroyed by penetrating acidic gastric juice, i.e.the acid resistance of the enteric coating layer of the pellets will notbe sufficient in the tablet after compression.

SUMMARY OF THE INVENTION

The present invention provides oral, fixed unit dosage forms, i.e. amultiple unit tableted dosage forms, multilayered tablets or a capsulefilled with more than one pharmaceutically active compound. The activecompounds present in the dosage form are preferably an acid susceptibleproton pump inhibitor which is protected by an enteric coating layer,and one or more prokinetic agents. These new dosage forms will simplifythe regimen and improve the patient compliance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a cross-section of a multiple unit tableted dosageform comprising an acid susceptible proton pump inhibitor in the form ofenteric coating layered pellets (1) in admixture with a prokinetic agentand pharmaceutically acceptable excipients (2). The tablet is covered bya filmcoating layer, i.e. tablet coat (7).

FIG. 2 illustrates a cross-section of a tablet with two separate layers,one of which comprising enteric coating layered pellets (1) in admixturewith excipients (3) and the other layer comprising the prokinetic agentin admixture with pharmaceutically acceptable excipients (2). The tabletis covered by a filmcoating layer (7).

FIG. 3 illustrates a cross-section of an enteric coating layered tabletcomprising a proton pump inhibitor in admixture with pharmaceuticallyacceptable excipients in the tablet core (5) surrounded by an entericcoating layer (8) and thereupon a layer of the prokinetic agent(s) inadmixture with pharmaceutically acceptable excipients (6). The tablet iscovered by a filmcoating layer (7).

FIG. 4 illustrates a cross-section of a multiple unit tableted dosageform comprising an acid susceptible proton pump inhibitor in the form ofenteric coating layered pellets (1) in admixture with excipients (3) andon the multiple unit tableted dosage form a layer comprising theprokinetic agent(s) in admixture with pharmaceutically acceptableexcipients (6). The tablet is covered by a filmcoating layer (7).

DETAILED DESCRIPTION OF THE INVENTION

One object of the invention is to provide an oral, multiple unittableted dosage form comprising an acid susceptible proton pumpinhibitor in the form of individually enteric coating layered unitstogether with one or more prokinetic agents in the form of a powder orgranules compressed into a tablet. The enteric coating layer(s) coveringthe individual units of the proton pump inhibitor has properties suchthat the compression of the units into a tablet does not significantlyaffect the acid resistance of the individually enteric coating layeredunits. Furthermore, the multiple unit tableted dosage form provides agood stability of the active substances during long-term storage.

The new fixed dosage form is preferably in the form of a multiple unittableted dosage form comprising enteric coating layered units of the oneof the active substance which is acid susceptible and granules of theother active substance, i.e. prepared prokinetic granules as shown inFIG. 1.

The proton pump inhibitor, in the form of enteric coating layered units,may also be mixed with pharmaceutically acceptable excipients andcompressed into a tablet which is then filmcoated with an aqueoussuspension containing the prokinetic substance, see FIG. 4.

Another object of the invention is to provide a tablet preparationcomprising a proton pump inhibitor in admixture with tablet excipientsin a tablet core and a separate layer surrounding the tablet core, whichlayer comprises one or more prokinetic agent(s) presscoated onto thetablet core. The tablet core is enteric coating layered before thesurrounding layer of prokinetic agents is applied. Optionally aseparating layer also is applied on the tablet before the entericcoating layer, see FIG. 3.

Alternatively, the prepared tablet is sectioned in separate layers, eachone comprising different active substances. Preferably one layercomprises the proton pump inhibitor in the form of enteric coatinglayered pellets in admixture with pharmaceutically acceptable excipientsand another layer(s) comprises(-e) the prokinetic agent(s) in admixturewith pharmaceutically acceptable excipients, respectively, see FIG. 2.

A further object of the invention is to provide a multiple unit tableteddosage form, which is divisible and easy to handle. Such a multiple unittableted dosage form may be dispersed in an aqueous liquid and can begiven to patients with swallowing disorders and in pediatrics. Such asuspension of dispersed units/pellets of appropriate size can be usedfor oral administration and also for feeding through a naso-gastrictube.

Furthermore, the present invention provides a capsule preparationcomprising the proton pump inhibitor in the form of enteric coatinglayered pellets mixed with one or more prokinetic agents in the form ofprepared granules or pellets. The new fixed unit dosage forms compriseas active substances one gastric acid suppressing agent, such as an acidsusceptible proton pump inhibitor and one or more prokinetic agents. Thedifferent therapeutically active components used in the dosage forms aredefined below.

The prokinetic part of the formulation may be formulated in the form ofinstant release, sustained release or extended release formulations.Alternatively, all the components of the formulation may be formulatedin an effervescent formulation.

ACTIVE SUBSTANCES

The gastric acid suppressing agent is preferably an acid susceptibleproton pump inhibitor. Such proton pump inhibitors are for examplecompounds of the general formula I ##STR1## wherein ##STR2## wherein Nin the benzimidazole moiety means that one of the carbon atomssubstituted by R₆ -R₉ optionally may be exchanged for a nitrogen atomwithout any substituents;

R₁, R₂ and R₃ are the same or different and selected from hydrogen,alkyl, alkoxy optionally substituted by fluorine, alkylthio,alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl andphenylalkoxy;

R₄ and R₅ are the same or different and selected from hydrogen, alkyland aralkyl; R₆ ' is hydrogen, halogen, trifluoromethyl, alkyl andalkoxy; R₆ -R₉ are the same or different and selected from hydrogen,alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl,oxazolyl, trifluoroalkyl, or adjacent groups R₆ -R₉ form ring structureswhich may be further substituted;

R₁₀ is hydrogen or forms an alkylene chain together with R₃ and R₁₁ andR₁₂ are the same or different and selected from hydrogen, halogen oralkyl, alkyl groups, alkoxy groups and moities thereof, they may bebranched or straight C₁ -C₉ -chains or comprise cyclic alkyl groups,such as cycloakylalkyl.

Examples of proton pump inhibitors according to formula I are ##STR3##

The proton pump inhibitors used in the dosage forms of the invention maybe used in neutral form or in the form of an alkaline salt, such as forinstance the Mg^(2+') Ca²⁺ ', Na⁺, K⁺ or Li⁺ salts, preferably the Mg²⁺salts. Further where applicable, the compounds listed above may be usedin racemic form or in the form of a substantially pure enantiomerthereof, or alkaline salts of the single enantiomers.

Suitable proton pump inhibitors are for example disclosed inEP-Al-0005129, EP-Al- 174 726, EP-Al-166 287, GB 2 163 747 andWO90/06925, WO91/19711, WO91/19712, and further especially suitablecompounds are described in WO95/01977 and WO94/27988.

The gastric acid suppressing agent is preferably an acid susceptibleproton pump inhibitor but other gastric acid suppressing agents such asthe H₂ receptor antagonists: ranitidine, cimetidine or famotidine, maybe used together with a prokinetic agent in the pharmaceuticalcompositions according to the present invention.

A wide variety of prokinetic compounds may be used in combination with asuitable proton pump inhibitor in the fixed unit dosage form accordingto the present invention. Such prokinetic agents include for examplecisapride, mosapride, metoclopramide, and domperidone. The activeprokinetic agents could be in standard forms or used as salts, hydrates,esters etc. A combination of two or more of the above described drugsmay be used. A preferable prokinetic agent for the new fixed dosage formis mosapride or cisapride. Such suitable prokinetic agents are describedin EP 0 243 959 and EP 0 076 530.

The preferred multiple unit tableted dosage form comprising a protonpump inhibitor in the form of a racemate, an alkaline salt or one of itssingle enantiomers in combination with a prokinetic compound, ischaracterized in the following way. Individually enteric coating layeredunits (small beads, granules or pellets) containing the proton pumpinhibitor and optionally alkaline reacting substances, are mixed withthe prokinetic compound and conventionally tablet excipients. Theprokinetic compound and tablet excipients may be dry mixed or wet-mixedinto granules. The mixture of enteric coating layered units, prokineticagent(s) and optionally excipients are compressed into the multiple unittableted dosage forms. With the expression "individual units" is meantsmall beads, granules or pellets, in the following referred to aspellets of the proton pump inhibitor.

The compaction process (compression) for formulating the multiple unittableted dosage form must not significantly affect the acid resistanceof the enteric coating layered pellets. In other words the mechanicalproperties, such as the flexibility and hardness as well as thethickness of the enteric coating layer(s), must secure that therequirements on enteric coated articles in the United StatesPharmacopeia are accomplished in that the acid resistance does notdecrease more than 10% during the compression of the pellets intotablets.

The acid resistance is defined as the amount of proton pump inhibitor inthe tablets or pellets after being exposed to simulated gastric fluidUSP, or to 0.1 M HCl (aq) relative to that of unexposed tablets andpellets, respectively. The test is accomplished in the following way.Individual tablets or pellets are exposed to stimulated gastric fluid ofa temperature of 37° C. The tablets disintegrate rapidly and release theenteric coating layered pellets to the medium. After two hours theenteric coating layered pellets are removed and analyzed for content ofthe proton pump inhibitor using High Performance Liquid Chromatography(HPLC).

Further specific components used in the fixed unit dosage forms of thepresent invention are defined below.

Core material--for Enteric Coating Layered Pellets Comprising a ProtonPump Inhibitor

The core material for the individually enteric coating layered pelletscan be constituted according to different principles. Seeds layered withthe proton pump inhibitor, optionally mixed with alkaline substances,can be used as the core material for the further processing.

The seeds which are to be layered with the proton pump inhibitor can bewater insoluble seeds comprising different oxides, celluloses, organicpolymers and other materials, alone or in mixtures or water-solubleseeds comprising different inorganic salts, sugars, non-pareils andother materials, alone or in mixtures. Further, the seeds may comprisethe proton pump inhibitor in the form of crystals, agglomerates,compacts etc. The size of the seeds is not essential for the presentinvention but may vary between approximately 0.1 and 2 mm. The seedslayered with the proton pump inhibitor are produced either by powder orsolution/suspension layering using for instance granulation or spraycoating layering equipment.

Before the seeds are layered, the proton pump inhibitor may be mixedwith further components. Such components can be binders, surfactantsfillers, disintegrating agents, alkaline additives or other and/orpharmaceutically acceptable ingredients alone or in mixtures. Thebinders are for example polymers such as hydroxypropyl methylcellulose(HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose sodium,polyvinyl pyrrolidone (PVP), or sugars, starches or otherpharmaceutically acceptable substances with cohesive properties.Suitable surfactants are found in the groups of pharmaceuticallyacceptable non-ionic or ionic surfactants such as for instance sodiumlauryl sulfate.

Alternatively, the proton pump inhibitor optionally mixed with alkalinesubstances and further mixed with suitable constituents can beformulated into a core material. Said core material may be produced byextrusion/spheronization, balling or compression utilizing conventionalprocess equipment. The size of the formulated core material isapproximately between 0.1 and 4 mm and preferably between 0.1 and 2 mm.The manufactured core material can further be layered with additionalingredients comprising the proton pump inhibitor and/or be used forfurther processing.

The proton pump inhibitor is mixed with pharmaceutical constituents toobtain preferred handling and processing properties and a suitableconcentration of the substance in the final mixture. Pharmaceuticalconstituents such as fillers, binders, lubricants, disintegratingagents, surfactants and other pharmaceutically acceptable additives.

Further, the proton pump inhibitor may also be mixed with an alkaline,pharmaceutically acceptable substance (or substances). Such substancescan be chosen among, but are not restricted to substances such as thesodium, potassium, calcium, magnesium and aluminium salts of phosphoricacid, carbonic acid, citric acid or other suitable weak inorganic ororganic acids; aluminium hydroxide/sodium bicarbonate coprecipitate;substances normally used in antacid preparations such as aluminium,calcium and magnesium hydroxides; magnesium oxide or compositesubstances, such as Al₂ O₃.6MgO.CO₂.12H₂ O, (Mg₆ Al₂ (OH)₁₆ CO₃.4H₂ O),MgO.Al₂ O₃.2SiO₂.nH₂ O or similar comp pH-buffering substances such astrihydroxymethyl-aminomethane, basic amino acids and their salts orother similar, pharmaceutically acceptable pH-buffering substances.

Alternafively, the aforementioned core material can be prepared by usingspray drying or spray congealing technique.

Enteric Coating Layer(s)

Before applying the enteric coating layer(s) onto the core material inthe form of individual pellets or tablets, the pellets or tablets mayoptionally be covered with one or more separating layer(s) comprisingpharmaceutical excipients optionally including alkaline compounds suchas pH-buffering compounds. This/these separating layer(s), separate(s)the core material from the outer layers being enteric coating layer(s).The separating layer(s) protecting the core material of a proton pumpinhibitor should be water soluble or rapidly disintegrating in water.

The separating layer(s) can be applied to the core material by coatingor layering procedures in suitable equipments such as coating pan,coating granulator or in a fluidized bed apparatus using water and/ororganic solvents for the coating process. As an alternative theseparating layer(s) can be applied to the core material by using powdercoating technique. The materials for the separating layers arepharmaceutically acceptable compounds such as, for instance, sugar,polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate, hydroxypropyl cellulose, methylcellulose, ethyl-cellulose,hydroxypropyl methyl cellulose, carboxymethylcellulose sodium andothers, used alone or in mixtures. Additives such as plasticizers,colorants, pigments, fillers anti-tacking and anti-static agents, suchas for instance magnesium stearate, titanium dioxide, talc and otheradditives may also be included into the separating layer(s).

When the optional separating layer, is applied to the core material itmay constitute a variable thickness. The maximum thickness of theseparating layer(s) is normally only limited by processing conditions.The separating layer may serve as a diffusion barrier and may act as apH-buffering zone. The pH-buffering properties of the separatinglayer(s) can be further strengthened by introducing into the layer(s)substances chosen from a group of compounds usually used in antacidformulations such as, for instance, magnesium oxide, hydroxide orcarbonate, aluminium or calcium hydroxide, carbonate or silicate;composite aluminium/magnesium compounds such as, for instance Al₂O₃.6MgO.CO₂.12H₂ O, (Mg₆ Al₂ (OH)₁₆ CO₃.4H₂ O), MgO.Al₂ O₃.2SiO₂.nH₂ O,aluminium hydroxide/sodium bicarbonate coprecipitate or similarcompounds; or other pharmaceutically acceptable pH-buffering compoundssuch as, for instance the sodium, potassium, calcium, magnesium andaluminium salts of phosphoric, carbonic, citric or other suitable, weak,inorganic or organic acids; or suitable organic bases, including basicamino acids and salts thereof Talc or other compounds may be added toincrease the thickness of the layer(s) and thereby strenghten thediffusion barrier. The optionally applied separating layer(s) is notessential for the invention. However, the separating layer(s) mayimprove the chemical stability of the active substance and/or thephysical properties of the novel multiple unit tableted dosage form.

Alternatively, the separating layer may be formed in situ by a reactionbetween an enteric coating polymer layer applied on the core material analkaline reacting compound in the core material. Thus, the separatinglayer formed comprises a salt formed between the enteric coating layerpolymer(s) and an alkaline reacting compound which is in the position toform a salt.

One or more enteric coating layers are applied onto the core material oronto the core material covered with separating layer(s) by using asuitable coating technique. The enteric coating layer material may bedispersed or dissolved in either water or in suitable organic solvents.As enteric coating layer polymers one or more, separately or incombination, of the following can be used, e.g. solutions or dispersionsof methacrylic acid copolymers, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl acetate phthalate, cellulose acetatetrimellitate, carboxymethylethylcellulose, shellac or other suitableenteric coating polymer(s).

The enteric coating layers may contain pharmaceutically acceptableplasticizers to obtain the desired mechanical properties, such asflexibility and hardness of the enteric coating layers. Suchplasticizers are for instance, but not restricted to triacetin, citricacid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol,polyethylene glycols, polysorbates or other plasticizers.

The amount of plasticizer is optimized for each enteric coating layerformula, in relation to selected enteric coating layer polymer(s),selected plasticizer(s) and the applied amount of said polymer(s), insuch a way that the mechanical properties, i.e. flexibility and hardnessof the enteric coating layer(s), for instance exemplified as Vickershardness, are adjusted so that the acid resistance of the pelletscovered with enteric coating layer(s) does not decrease significantlyduring compression of pellets into tablets. The amount of plasticizer isusually above 10% by weight of the enteric coating layer polymer(s),preferably 15-50% and more preferably 20-50%. Additives such asdispersants, colorants, pigments polymers e.g. poly (ethylacrylate,methylinethacrylate), anti-tacking and anti-foaming agents may also beincluded into the enteric coating layer(s). Other compounds may be addedto increase film thickness and to decrease diffusion of acidic gastricjuices into the acid susceptible material.

To protect the acid susceptible substance, the proton pump inhibitor,and to obtain an acceptable acid resistance of the dosage form accordingto the invention, the enteric coating layer(s) constitutes a thicknessof approximately at least 10 μm, preferably more than 20 μm. The maximumthickness of the applied enteric coating is normally limited byprocessing conditions and the desired dissolution profile.

Alternatively the enteric coating layer described above may be used forenteric coating of conventional tablets comprising an acid susceptibleproton pump inhibitor. Said enteric coating layered tablet is thereafterpresscoated with a granulation comprising the prokinetic compound.

Over-coating Layer

Pellets covered with enteric coating layer(s) may further be coveredwith one or more over-coating layer(s). The over-coating layer(s) shouldbe water soluble or rapidly disintegrating in water. The over-coatinglayer(s) can be applied to the enteric coating layered pellets bycoating or layering procedures in suitable equipments such as coatingpan, coating granulator or in a fluidized bed apparatus using waterand/or organic solvents for the coating or layering process. Thematerials for over-coating layers are chosen among pharmaceuticallyacceptable compounds such as, for instance sugar, polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and others, used aloneor in mixtures. Additives such as plasticizers, colorants, pigments,fillers, anti-tacking and anti-static agents, such for instancemagnesium stearate, titaniumdioxide, talc and other additives may alsobe included into the over-coating layer(s). Said over-coating layer mayfurther prevent potential agglomeration of enteric coating layeredpellets, further protect the enteric coating layer towards crackingduring the compaction process and enhance the tableting process. Themaximum thickness of the applied over-coating layer(s) is normallylimited by processing conditions and the desired dissolution profile.

The above described over-coating layer may also be used as a tabletfilmcoat to obtain tablets of good appearance.

Prokinetic Preparation

The active substance(s) in form of one or more prokinetic compound(s) isdry mixed with inactive excipients and the mixture is wet massed with agranulation liquid. The wet mass is dried preferably to a loss on dryingof less than 3% by weight. Thereafter the dry mass is milled to asuitable size for the granules, such as smaller than 4 mm, andpreferably smaller than 1 mm. Suitable inactive excipients for theprokinetic mixture are for instance lactose, corn starch low substitutedhydroxypropyl cellulose, microcrystalline cellulose, sodium starchglycolate and crosslinked polyvinyl pyrrolidone. The dry mixturecomprising prokinetic compound is wet-mixed with a suitable granulationliquid comprising for instance hydroxy propyl cellulose or polyvinylpyrrolidone dissolved in purified water or an alcohol or a mixturethereof. Alternatively, the prokinetic agent(s) are dry mixed withpharmaceutically acceptable excipients according to above.

As a further alternative, the prokinetic agent(s) can be applied in aseparate layer onto a multiple unit tableted dosage form or surroundingthe tablet comprising the proton pump inhibitor. The prokinetic agent(s)is dispersed or dissolved in an aqueous solution optionally comprisingbinders for suspension layering onto the tablet.

Multiple Unit Tablets

The enteric coating layered pellets comprising a proton pump inhibitorare mixed with the granules comprising prokinetic compound and tabletexcipients such as fillers, binders, disintegrants, lubricants and otherpharmaceutically acceptable additives. The mixture is compressed into amultiple unit tableted dosage form. The compressed tablet is optionallycovered with a filmforming agent(s) to obtain a smooth surface of thetablet and further enhance the stability of the tablet during packagingand transport. Such a coating layer may further comprise additives suchas anti-tacking agents, colorants and pigments or other additives toobtain a tablet of good appearance.

Alternatively the enteric coated pellets may be dry mixed with theprokinetic compound and pharmaceutically acceptable tablet excipientsaccording to above, and compressed into tablets (direct compression).

Suitable lubricants for the tableting process are for instance sodiumstearyl fumarate, magnesium stearate and talc.

Further, the different active substances may be formulated intodifferent layers, wherein the layer comprising the proton pump inhibitoris in the form of a multiple unit tableted dosage form layered withprepared prokinetic granules. The two layers may be separated by ananti-tacking layer.

As a further alternative the proton pump inhibitor is dry mixed withinactive excipients and compressed into a conventional tablet which iscoating layered with an enteric coating and optionally a separatinglayer is applied before the enteric coating. Thereafter the entericcoated tablet is presscoated with a prokinetic preparation. The tabletcore may also be formulated as a multiple unit tableted dosage formcomprising the proton pump inhibitor, the tablet is spray coatinglayered by a suspension comprising the prokinetic agent(s).

The fraction of enteric coating layered pellets constitutes less than75% by weight of the total tablet weight and preferably less than 60%.By increasing the amount of the granules comprising the prolinetic agentthe fraction of enteric coating layered pellets of the proton pumpinhibitor may be reduced in the multiple unit tableted dosage form. Bychoosing small enteric coating layered pellets in the formulationaccording to the present invention, the number of pellets in each tabletcan be held high which in turn makes the tablet divisible with retaineddosing accuracy.

Thus, the preferred multiple unit tablet formulation consists of entericcoating layered pellets containing one active substance in the form of aproton pump inhibitor, optionally admixed with alkaline reactingcompound(s), compressed into tablets together with the preparedprokinetic mixture and optionally tablet excipients. The addition of analkaline reacting material to the proton pump inhibitor is notnecessary, in any sense but such a substance may further enhance thestability of the proton pump inhibitor or some of the alkaline reactingcompounds may react in situ with the enteric coating material to form aseparating layer. The enteric coating layer(s) is making the pellets ofthe dosage form insoluble in acidic media, but disintegrating/dissolvingin near neutral to alkaline media such as, for instance the liquidspresent in the proximal part of the small intestine, where dissolutionof the proton pump inhibitor is desired. The prokinetic agent(s) may bereleased in the stomach. The enteric coating layered pellets may furtherbe covered with an overcoating layer before being formulated into thetablet and they may also contain one or more separating layer(s)optionally containing alkaline substance(s).

Process

The process for the manufacture of the dosage form represents a furtheraspect of the invention. After formulation of the pellets by spraycoating or layering of the proton pump inhibitor onto seeds, or byextrusion/spheronization or granulation, e.g. rotor granulation ofhomogeneous pellets, the pellets are first optionally covered with theseparating layer(s) and then with the enteric coating layer(s) or aseparating layer is spontaneously developed in situ between the alkalinecore material and the enteric coating layer material. The coating iscarried out as described above and in the accompanying examples. Thepreparation of the prokinetic mixture is also described above and in theexamples. The pharmaceutical processes can preferably be completelywater-based.

The enteric coating layered pellets, with or without an over-coat, aremixed with the prepared prokinetic mixture, optionally tablet excipientsand other pharmaceutically acceptable additives and compressed intotablets. Alternatively, the enteric coating layered pellets may beintimately mixed with tablet excipients and precompressed and furtherlayered with the prepared prokinetic mixture and finally compressed intoa tablet. As a further alternative the proton pump inhibitor in form ofthe active substance may be mixed with tablet excipients and compressedinto a tablet which is optionally layered with a separating layer andthereafter enteric coating layered. Said tablet is then presscoated withthe prepared prokinetic mixture. Alternatively, a multiple unit tableteddosage form of the proton pump inhibitor is manufactured as describesabove. The multiple unit dosage form is spray coating layered by anaqueous suspension comprising the prokinetic agent(s). The suspensionmay optionally comprise binders; such as hydroxypropyl methylcellulose,and an alcohol to solve the binder. The proton pump inhibitor in theform of enteric coating layered pellets may also be filled into acapsule together with the prokinetic substance in the form of agranulation optionally mixed with pharmaceutical excipients.

Use of the Preparation

The dosage forms according to the invention are especially advantageousin the treatment of gastro oesophageal reflux disease and othergastrointestinal disorder. They are administered one to several times aday, preferably once or twice daily. The typical daily dose of theactive substances varies and will depend on various factors such as theindividual requirements of the patients, the mode of administration anddisease. In general each dosage form will comprise 0.1-200 mg of theproton pump inhibitor and 0.1-100 mg of the prokinetic compound.Preferably, each dosage form will comprise 10-80 mg of the proton pumpinhibitor and 3-80 mg of the prokinetic compound, and more preferably10-40 mg of proton pump inhibitor and 15-40 mg of the prokineticcompound, respectively.

The multiple unit tablet preparation is also suitable for dispersion inan aqueous liquid with slightly acidic pH-value before being orallyadministered or fed through a naso-gastric tube.

The invention is illustrated more in detail in the following examples.

EXAMPLES Example 1

Multiple unit dosage form comprising magnesium omeprazole and mosapride(batch size 500 tablets).

    ______________________________________                                        Core material                                                                 Magnesium omeprazole      5      kg                                           Sugar sphere seeds        10     kg                                           Hydroxypropyl methylcellulose                                                                           0.75   kg                                           Water purified            20.7   kg                                           Separating layer                                                              Core material (acc. to above)                                                                           10.2   kg                                           Hydroxypropyl cellulose   1.02   kg                                           Talc                      1.75   kg                                           Magnesium stearate        0.146  kg                                           Water purified            21.4   kg                                           Enteric coating layer                                                         Pellets covered with separating layer                                                                   11.9   kg                                           (acc. to above)                                                               Methacrylic acid copolymer (30% suspension)                                                             19.8   kg                                           Triethyl citrate          1.79   kg                                           Mono- and diglycerides (NF)                                                                             0.297  kg                                           Polysorbate 80            0.03   kg                                           Water purified            11.64  kg                                           Over-coating layer                                                            Enteric coating layered pellets                                                                         20     kg                                           (acc. to above)                                                               Hydroxypropyl methylcellulose                                                                           0.238  kg                                           Magnesium stearate        0.007  kg                                           Water purified            6.56   kg                                           Tablets                                                                       Prepared pellets comprising omeprazole                                                                  41.2   g                                            (acc. to above)                                                               Mosapride citrate dihydrate                                                                             23.4   g                                            Microcrystalline cellulose                                                                              138.1  g                                            Polyvinyl pyrrolidone crosslinked                                                                       2.9    g                                            Sodium stearyl fumarate   0.29   g                                            Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methylcellulose                                                                           250    g                                            Polyethylene glycol 6000  62.5   g                                            Titanium dioxide          62.5   g                                            Water purified            2125   g                                            Hydrogen pyroxide         0.75   g                                            ______________________________________                                    

Suspension layering was performed in a fluid bed apparatus. Magnesiumomeprazole was sprayed onto sugar sphere seeds from a water suspensioncontaining the dissolved binder. The size of sugar sphere seeds were inthe range of 0.25 to 0.35 mm.

The prepared core material was covered with a separating layer in afluid bed apparatus with a hydroxypropyl cellulose solution containingtalc and magnesium stearate. The enteric coating layer consisting ofmethacrylic acid copolymer, mono- and diglycerides, triethyl citrate andpolysorbate was sprayed onto the pellets covered with a separating layerin a fluid bed apparatus. In a fluid bed apparatus enteric coatinglayered pellets were coated with a hydroxypropyl methylcellulosesolution containing magnesium stearate. The over-coating layered pelletswere classified by sieving.

The enteric coating layered pellets with an over-coating layer,mosapride citrate dihydrate, microcrystalline cellulose, polyvinylpyrrolidone crosslinked and sodium stearyl fumarate were dry mixed andcompressed into tablets using an excenter tableting machine equippedwith 12 mm punches. The amount of omeprazole in each tablet was approx.10 mg and the amount of mosapride was approx. 30 mg. The tablet hardnesswas measured to 70-80 N.

The obtained tablets are covered with a conventional tablet filmcoatinglayer.

Example 2

Multiple unit dosage form comprising magnesium omeprazole and mosapride(batch size 500 tablets).

    ______________________________________                                        Mosapride granulation                                                         Mosapride citrate dihydrate                                                                              46.8   g                                           Lactose monohydrate        350    g                                           Corn starch                184    g                                           Hydroxy propyl cellulose LF                                                                              25     g                                           Water purified             225    g                                           Hydroxypropyl cellulose (L-HPC)                                                                          152    g                                           Magnesium stearate         7.4    g                                           Tablets                                                                       Enteric coating layered pellets with an over-coating layer                                               41.2   g                                           (manufacturing and composition as in example 1)                               Mosapride granulation      190    g                                           Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methyl cellulose                                                                           250    g                                           Polyethylene glycol 6000   62.5   g                                           Titaniumdioxid             62.5   g                                           Water purified             2125   g                                           Hydrogen peroxide          0.75   g                                           ______________________________________                                    

Hydroxypropyl cellulose was dissolved in purified water to form thegranulation liquid. Mosapride citrate dihydrate, lactose monohydrate andcorn starch were dry mixed. The granulation liquid was added to thepowder mixture and the mass was wet-mixed. The wet mass was dried in asteam-oven and milled through sive 1 mm in an oscillating mill equipmentThe prepared granulation was mixed with low substituted hydroxypropylcellulose and magnesium stearate.

The enteric coating layered pellets with an over-coat and preparedgranules were mixed and compressed into tablets using an excentertableting machine equipped with 11 mm punches. The amount of omeprazolein each tablet was approx. 10 mg and the amount of mosapride was approx.15 mg. Tablet hardness was measured to 30-40 N.

The obtained tablets are covered with a conventional tablet filmcoatinglayer.

Example 3

Multiple unit dosage form comprising magnesium omeprazole and mosapride(batch size 500 tablets).

    ______________________________________                                        Core material                                                                 Magnesium omeprazole      10      kg                                          Sugar sphere seeds        10      kg                                          Hydroxypropyl methylcellulose                                                                           1.5     kg                                          Water purified            29.9    kg                                          Separating layer                                                              Core material (acc. to above)                                                                           20      kg                                          Hydroxypropyl cellulose   2       kg                                          Talc                      3.43    kg                                          Magnesium stearate        0.287   kg                                          Water purified            41      kg                                          Enteric coating layer                                                         Pellets covered with separating layer (acc. to above)                                                   24.5    kg                                          Methacrylic acid copolymer (30% suspension)                                                             32.7    kg                                          Triethyl citrate          2.94    kg                                          Mono-and diglycerides (NF)                                                                              0.49    kg                                          Polysorbate 80            0.049   kg                                          Water purified            19.19   kg                                          Over-coating layer                                                            Enteric coating layered pellets (acc. to above)                                                         37.8    kg                                          Hydroxypropyl methylcellulose                                                                           0.49    kg                                          Magnesium stearate        0.0245  kg                                          Water purified            11.6    kg                                          Tablets                                                                       Prepared pellets comprising omeprazole (acc. to above)                                                  47.45   g                                           Mosapride citrate dihydrate                                                                             23.4    g                                           Microcrystalline cellulose                                                                              163     g                                           Polyvinyl pyrrolidone crosslinked                                                                       3.3     g                                           Sodium stearyl fumarate   0.3     g                                           Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methyl cellulse                                                                           250     g                                           Polyethylene glycol 6000  62.5    g                                           Titanium dioxid           62.5    g                                           Water purified            2125    g                                           Hydrogen peroxide         0.75    g                                           ______________________________________                                    

The enteric coating layered pellets with an over-coating layer preparedas described in Example 1, mosapride citrate dihydrate, microcrystallinecellulose, polyvinyl pyrrolidone crosslinked and sodium stearyl fumaratewere dry mixed and compressed into tablets using an excenter tabletingmachine equipped with 12 mm punches. The amount of omeprazole in eachtablet was approx. 20 mg and the amount of mosapride was approx. 30 mg.The tablet hardness was measured to 70 N.

The tablets are covered with a conventional tablet filmcoating layer.

Example 4

Multiple unit dosage form comprising S-omeprazole magnesium salt andmosapride (batch size 300 tablets).

    ______________________________________                                        Core material                                                                 S-omeprazole magnesium salt                                                                             120    g                                            Sugar sphere seeds        150    g                                            Hydroxypropyl methylcellulose                                                                           18     g                                            Polysorbate 80            2.4    g                                            Water purified            562    g                                            Separating layer                                                              Core material (acc. to above)                                                                           200    g                                            Hydroxypropyl cellulose   30     g                                            Talc                      51.4   g                                            Magnesium stearate        4.3    g                                            Water purified            600    g                                            Enteric coating layer                                                         Pellets covered with separating layer                                                                   250    g                                            (acc. to above)                                                               Methacrylic acid copolymer (30% suspension)                                                             333.7  g                                            Triethyl citrate          30     g                                            Mono- and diglycerides (NF)                                                                             5      g                                            Polysorbate 80            0.5    g                                            Water purified            196    g                                            Tablets                                                                       Prepared pellets comprising (s)-omeprazole Mg-salt                                                      38.2   g                                            (acc. to above)                                                               Mosapride citrate dihydrate                                                                             14     g                                            Microcrystalline cellulose                                                                              98.3   g                                            Polyvinyl pyrrolidone crossliriked                                                                      2.1    g                                            Sodium stearyl fumarate   0.2    g                                            Tablet coating solution (for 10 kg tablet)                                    Hydroxypropyl methyl cellulose                                                                          250    g                                            Polyethylene glycol 6000  62.5   g                                            Titaniumdioxid            62.5   g                                            Water purified            2125   g                                            Hydrogen peroxide         0.75   g                                            ______________________________________                                    

Suspension layering was performed in a fluid bed apparatus. S-Omeprazolemagnesium salt was sprayed onto sugar sphere seeds from a watersuspension containing the dissolved binder and polysorbate 80. The sizeof sugar sphere seedes were in the range of 0.25 to 0.35 mm.

The prepared core material was covered with a separating layer in afluid bed apparatus with hydroxypropyl cellulose solution containingtalc and magnesium stearate. The enteric coating layer consisting ofmethacrylic acid copolymer, mono-and diglycerides, triethyl citrate andpolysorbate was sprayed onto the pellets covered with a separating layerin a fluid bed apparatus. The enteric coating layered pellets wereclassified by sieving.

The enteric coating layered pellets, mosapride citrate dihydrate,microcrystalline cellulose, polyvinyl pyrrolidone crosslinked and sodiumstearyl fumarate were mixed and compressed into tablets using anexcenter tableting machine equipped with 12 mm punches. The amount ofS-omeprazole in each tablet was approx. 20 mg and the amount ofmosapride was approx. 30 mg. The tablet hardness was measured to 65 N.

The tablets are covered with a conventional tablet filmcoating layer.

    ______________________________________                                        "Acid resistance" i.e. %                                                      left after exposure to 0.1 N                                                  HCl for 2 hrs                                                                            Tablets                                                            ______________________________________                                                Ex 1  97%                                                                     Ex 2  90%                                                                     Ex 3 102%                                                                     Ex 4 104%                                                             ______________________________________                                    

Example 5

Multiple unit dosage form comprising lanzoprazole and mosapride (batchsize 500 tablets).

    ______________________________________                                        Core material                                                                 Lanzoprazole               400    g                                           Sugar sphere seeds         400    g                                           Hydroxypropyl methylcellulose                                                                            80     g                                           Sodium laurylsulfate       3      g                                           Water purified             1500   g                                           Separating layer                                                              Core material (acc. to above)                                                                            400    g                                           Hydroxypropyl cellulose    40     g                                           Talc                       69     g                                           Magnesium stearate         6      g                                           Water purified             800    g                                           Enteric coating layer                                                         Pellets covered with a separating layer (acc. to above)                                                  400    g                                           Methacrylic acid copolymer (30% suspension)                                                              667    g                                           Triethyl citrate           60     g                                           Mono- and diglycerides (NF)                                                                              10     g                                           Polysorbate 80             1      g                                           Water purified             420    g                                           Tablets                                                                       Prepared pellets comprising lanzoprazple (acc. to above)                                                 47     g                                           Mosapride citrate dihydrate                                                                              46.8   g                                           Microcrystalline cellulose 261    g                                           Polyvinyl pyrrolidone crosslinked                                                                        5      g                                           Sodium stearyl fumarate    0.5    g                                           Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methylcellulose                                                                            250    g                                           Polyethylene glycol 6000   62.5   g                                           Titanium dioxid            62.5   g                                           Water purified             2125   g                                           Hydrogen peroxide          0.75   g                                           ______________________________________                                    

Suspension layering was performed in a fluid bed apparatus. Lansoprazolewas sprayed onto the sugar sphere seeds from a suspension containing thedissolved binder in a water solution. Pellets covered with separatinglayer and enteric coating layer were produced as in example 1.

The enteric coating layered pellets, mosapride citrate dihydrate,microcrystalline cellulose, polyvinyl pyrrolidone crosslinked and sodiumstearyl fumarate were dry mixed and compressed into tablets using anexcenter tableting machine equipped with 10 mm punches. The amount oflanzoprazole in each tablet was approx. 10 mg and the amount ofmosapride was approx. 30 mg. The tablet hardness was measured to 70 N.

The tablets are covered with a conventional tablet filmcoating layer.

Example 6

Magnesium omeprazole and mosapride presscoated tablets (batch size10.000 tablets).

    ______________________________________                                        Omeprazole tablets                                                            Mg-omeprazole             112.5   g                                           Mannitol                  287     g                                           Microcrystalline cellulose                                                                              94      g                                           Sodium starch glycolate   30      g                                           Hydroxypropyl methylcellulose                                                                           30      g                                           Talc                      25      g                                           Microcrystalline cellulose                                                                              31      g                                           Sodium stearyl fumarate   12.5    g                                           Water purified            200     g                                           Solution for separating layer (for 10 kg tablets)                             Hydroxypropyl methylcellulose                                                                           300     g                                           Hydrogen peroxide (30%)   0.003   g                                           Water purified            2700    g                                           Solution for enteric coating layer (for 10 kg tablets)                        Methacrylic acid copolymer dispersion (30%)                                                             2450    g                                           Polyethylene glycol 400   80      g                                           Titanium dioxide Colour   100     g                                           Water purified            1960    g                                           Presscoated tablet                                                            Mg-Omeprazole tablets     10.000  tabl                                        Mosapride granulation     3800    g                                           (manufacturing and composition as in example 2)                               Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methylcellulose                                                                           250     g                                           Polyethylene glycol 6000  62.5    g                                           Titaniumdioxid            62.5    g                                           Water purified            2125    g                                           Hydrogen peroxide         0.75    g                                           ______________________________________                                    

Magnesium omeprazole, mannitol, microcrystalline cellulose, sodiumstarch glycolate and hydroxypropyl methyl cellulose are dry mixed. Thepowder mixture is moistened with water purified. The granulation isdried and milled through sive 1 mm in a suitable mill. The preparedgranules comprising proton pump inhibitor is mixed with talc,microcrystalline cellulose and sodium stearyl fumarate and compressedinto tablets using a rotary tableting machine equipped with 5 mmpunches.

The obtained tablets are coated layered with a separating layer and anenteric coating layer. Said tablets are then presscoated with mosapridegranulation using a presscoating machine equipped with 11 mm punched.

The tablets are covered with a conventional tablet filmcoating layer.

Example 7

A capsule formulation comprising magnesium omeprazole and mosapride(batch size 100 capsules).

    ______________________________________                                        Capsules                                                                      Enteric coating layered pellets with an over-coating layer                                               9.49   g                                           (manufacturing and composition as in example 3)                               Mosapride granulation      38     g                                           (manufacturing and composition as in example 2)                               ______________________________________                                    

Enteric coating layered pellets and mosapride granulation are filledinto capsules, size 00. The amount of omeprazole in each capsule isapprox. 20 mg and the amount of mosapride is approx. 15 mg.

Example 8

Multiple unit dosage form comprising magnesium omeprazole with a tabletcoating layer comprising mosapride (batch size 1000 tablets).

    ______________________________________                                        Tablets                                                                       Enteric coating layered pellets with an overcoat                                                         82.4   g                                           (manufacturing and composition as in example 1)                               Microcrystalline cellulose 179.2  g                                           Polyvinyl pyrrolidone crosslinked                                                                        3.7    g                                           Sodium stearyl fumarate    0.4    g                                           Mosapride coating layer suspension                                            Mosapride citrate dihydrate                                                                              23.4   g                                           Hydroxypropyl methyl cellulose                                                                           13.4   g                                           Ethanol 99%                132.5  g                                           Water purified             132.5  g                                           Tablet coating solution (for 10 kg tablets)                                   Hydroxypropyl methylcellulose                                                                            250    g                                           Polyethylene glycol 6000   62.5   g                                           Titanium dioxid            62.5   g                                           Water purified             2125   g                                           Hydrogen peroxide          0.75   g                                           ______________________________________                                    

The enteric coating layered pellets are mixed with microcrystallinecellulose, polyvidone and sodium stearyl fumarate and compressed intotablets using an excenter tableting machine equipped with 9 mm punches.The tablets are then coated layered in a fluid bed apparatus with thesuspension comprising mosapride. The amount of omeprazole in each tabletis approx. 10 mg and the amount of mosapride is approx. 15 mg.

Finally the tablets are covered with a conventional tablet filmcoatinglayer.

The best mode to practise the invention is according to compositionsdescribed in Examples 1 and 4.

The enteric coating layered pellets comprising a proton pump inhibitormay also be prepared as described in the following examples.

Example 9

Preparation of enteric coating layered pellets byextrusion/spheronization.

    ______________________________________                                        Core material                                                                 Magnesium omeprazole    600    g                                              Mannitol                1000   g                                              Microcrystalline cellulose                                                                            300    g                                              Hydroxypropyl cellulose 100    g                                              Sodium lauryl sulphate  6      g                                              Water purified          802    g                                              Separating layer                                                              Core material           400    g                                              Hydroxypropyl methylcellulose                                                                         48     g                                              Water purified          960    g                                              Enteric coating layer                                                         Pellets covered with separating layer                                                                 200    g                                              Methacrylic acid copolymer                                                                            100    g                                              Triethyl citrate        30     g                                              Mono- and diglycerides (NF)                                                                           5      g                                              Polysorbate 80          0.5    g                                              Water purified          309    g                                              ______________________________________                                    

Sodium lauryl sulphate is dissolved in purified water to form thegranulation liquid. Magnesium omeprazole, mannitol, microcrystallinecellulose and hydroxypropyl cellulose are dry-mixed. The granulationliquid is added to the powder mixture and the mass is wet-mixed.

The wet mass is forced through an extruder equipped with screens of size0.5 mm. The extrudate is spheronized on a friction plate in aspheronizing apparatus. The core material is dried in a fluid bed dryerand classified. The prepared core material is covered by a separatinglayer in a fluid bed apparatus with a hydroxypropylmethylcellulose/water solution.

The enteric coating layer is applied to the pellets covered withseparating layer from an aqueous dispersion of methacrylic acidcopolymer plasticized with triethyl citrate to which a mono- anddiglycerides/polysorbate dispersion has been added. The pellets aredried in a fluid bed apparatus.

Example 10

Preparation of enteric coating layered pellets by powder.

    ______________________________________                                        Core material                                                                 Magnesium omeprazole    1500   g                                              Sugar sphere seeds      1500   g                                              Hydroxypropyl methylcellulose                                                                         420    g                                              Aerosil ®           8      g                                              Water purified          4230   g                                              Separating layer                                                              Core material           500    g                                              Hydroxypropyl cellulose 40     g                                              Talc                    67     g                                              Magnesium stearate      6      g                                              Water purified          800    g                                              Enteric coating layer                                                         Pellets covered with separating layer                                                                 500    g                                              Methacrylic acid copolymer                                                                            200    g                                              ______________________________________                                    

Magnesium omeprazole, part of the hydroxypropyl methylcellulose andAerosil® are dry-mixed forming a powder. Sugar sphere seeds (0.25-0.40mm) are layered with the powder in a centrifugal fluidized coatinggranulator while spraying a hydroxypropyl methylcellulose solution (6%,w/w).

The prepared core material is dried and covered by a separating layer ina centrifugal fluidized coating-granulator. A fluid bed apparatus isused for enteric coating layereing.

Example 11

Preparation of enteric coating layered pellets with of silicon dioxideseeds.

    ______________________________________                                        Core material                                                                 Magnesium omeprazole    8.00   kg                                             Silicon dioxide         8.00   kg                                             Hydroxypropyl methylcellulose                                                                         1.41   kg                                             Sodium lauryl sulphate  0.08   kg                                             Water purified          28.00  kg                                             Separating layer                                                              Core material           10.00  kg                                             Hydroxypropyl methylcellulose                                                                         0.80   kg                                             Water purified          10.00  kg                                             Enteric coating layer                                                         Pellets covered with separating layer                                                                 300    g                                              Methacrylic acid copolymer                                                                            124    g                                              Polyethylene glycol 400 25     g                                              Mono- and diglycerides (NF)                                                                           3      g                                              Polysorbate 80          1      g                                              Water purified          463    g                                              ______________________________________                                    

Suspension layering is performed in a fluid bed apparatus. Magnesiumomeprazole is sprayed onto the silicon dioxide seeds from a watersuspension containing the dissolved binder and a surface activeingredient.

The prepared core material is covered with a separating layer in a fluidbed apparatus with a hydroxypropyl methylcellulose solution. The entericcoating layer consisting of methacrylic acid copolymer, mono- anddiglycerides, polyethylene glycol 400 and polysorbate is sprayed ontothe pellets covered with separating layer in a fluid bed apparatus.

Example 12

Preparation of enteric coating layered pellets.

    ______________________________________                                        Enteric coating layer                                                         Pellets covered with separating layer                                                                 500    g                                              (manufacturing and composition                                                as in example 10)                                                             Methacrylic acid copolymer                                                                            250    g                                              Polyethylene glycol 6000                                                                              75     g                                              Mono- and diglycerides (NF)                                                                           12.5   g                                              Polysorbate 80          1.2    g                                              Water purified          490    g                                              ______________________________________                                    

Example 13

Preparation of enteric coating layered pellets.

    ______________________________________                                        Enteric coating                                                               Pellets covered with separating layer                                                                    500    g                                           (manufacturing and composition as in example 1)                                                          250    g                                           Hydroxypropyl methylcellulose phthalate                                       Cetanol                    50     g                                           Ethanol (95%)              1000   g                                           Acetone                    2500   g                                           ______________________________________                                    

Example 14

Preparation of enteric coating layered pellets.

    ______________________________________                                        Core material                                                                 Omeprazole                 225    g                                           Mannitol                   1425   g                                           Hydroxypropyl cellulose    60     g                                           Microcrystalline cellulose 40     g                                           Lactose anhydrous          80     g                                           Sodium lauryl sulphate     5      g                                           Disodium hydrogen phosphate dihydrate                                                                    8      g                                           Water purified             350    g                                           Separating layer                                                              Core material              300    g                                           Hydroxypropyl cellulose    30     g                                           Talc                       51     g                                           Magnesium stearate         4      g                                           Enteric coating layer                                                         Pellets covered with separating layer                                                                    300    g                                           Methacrylic acid copolymer 140    g                                           Triethyl citrate           42     g                                           Mono- and diglycerides (NF)                                                                              7      g                                           Polysorbate 80             0.7    g                                           ______________________________________                                    

The dry ingredients for producing the core material are well mixed in amixer. Addition of granulation liquid is made and the mixture is kneededand granulated to a proper consistency. The wet mass is pressed throughan extruder screen and the granules are converted into a spherical formin a spheronizer. The core material is dried in a fluid bed apparatusand classified into a suitable particle size range, e.g. 0.5-1.0 mm Theprepared core material is covered with a separating layer and entericcoating layered as described in previous examples.

Preparation of Active Substance

Magnesium omeprazole used in some of the examples is produced accordingto the process described in WO95/01977, the single enantiomers ofomeprazole salts are prepared as described in WO94/27988 and omeprazoleis produced according to the process disclosed in EP-Al 0005129. Thesedocuments are hereby incorporated in a whole by reference.

What is claimed is:
 1. An oral pharmaceutical composition comprising, asa first component, an acid susceptible proton pump inhibitor, and as aseparate second component, at least one prokinetic agent, and as anoptional third component, pharmaceutically acceptable excipients,wherein: (a) the composition is in the form of a multiple unit tablet;(b) the first component is in the form of pellets covered with anenteric coating layer; (c) the second component is separated from thefirst component by the enteric coating layer covering the firstcomponent; and (d) the enteric coating layer has mechanical propertiessuch that the acid resistance of the enteric coated pellets is notsignificantly affected by compression of the pellets with the othertablet components during tableting.
 2. The composition according toclaim 1, wherein the proton pump inhibitor is covered by a separatinglayer located underneath the enteric coating layer.
 3. The compositionaccording to claim 1, wherein the tableted dosage form comprises aproton pump inhibitor and one prokinetic agent.
 4. The compositionaccording to claim 1, wherein the proton pump inhibitor is omeprazole,an alkaline salt of omeprazole, a single enantiomer of omeprazole or analkaline salt of the single enantiomer.
 5. The composition according toclaim 4, wherein the proton pump inhibitor is S-omeprazole magnesiumsalt.
 6. The composition according to claim 1, wherein the proton pumpinhibitor is lansoprazole, an alkaline salt of lansoprazole, a singleenantiomer of lansoprazole or an alkaline salt of the single enantiomer.7. The composition according to any one of claims 4-6, wherein theprokinetic agent is mosapride.
 8. The composition according to any oneof claims 4-6, wherein the prokinetic agent is cisapride.
 9. Thecomposition according to claim 1, wherein the amount of the proton pumpinhibitor is in the range of 10-80 mg, and the amount of the secondcomponent is in the range of 3-80 mg.
 10. The composition according toclaim 1, wherein the amount of the proton pump inhibitor is in the rangeof 10-40 mg, and the amount of the second component is in the range of15-40 mg.
 11. The composition according to claim 1, wherein the tableteddosage form comprises a first layer comprising the proton pump inhibitorand a separate second layer comprising the second component.
 12. Thecomposition according to claim 1, wherein the acid resistance of theenteric coating layered pellets is in compliance with the requirementson enteric coating layered articles defined in the United StatesPharmacopeia.
 13. The composition according to claim 1, wherein the acidresistance of the enteric coating layered pellets does not decrease morethan 10% upon the tableting of the pellets into the multiple unit dosageform.
 14. The composition according to claim 1, wherein the entericcoating pellets comprises a plasticized enteric coating layer material.15. The composition according to claim 1, wherein the enteric coatinglayered pellets are further covered with an over-coating layercomprising pharmaceutically acceptable excipients.
 16. The compositionaccording to claim 1, wherein the tablet is divisible.
 17. Thecomposition according to claim 16, wherein the tablet is dispersible toform a slightly acidic aqueous suspension comprising the secondcomponent and the enteric coating pellets comprising a proton pumpinhibitor.
 18. The composition according to claim 1, wherein the protonpump inhibitor is in the form of a multiple unit dosage form layeredwith a coating layer comprising the second component.
 19. A process forthe manufacture of a composition in the form of a multiple unit tableteddosage form comprising, as a first component, a proton pump inhibitor,and as a separate second component, at least one prokinetic agent,comprising the steps of(a) preparing the proton pump inhibitor in theform of enteric coating layered pellets; (b) mixing the enteric coatedpellets with the second component and an optional pharmaceuticallyacceptable tablet excipient; and (c) compressing the mixture to form amultiple unit tablet without affecting any significant change of theacid resistance of the enteric coating layered pellets.
 20. A processfor the manufacture of a composition in the form of a multiple unittableted dosage form having separate layers and comprising, as a firstcomponent in one layer a proton pump inhibitor, and as a secondcomponent in a separate second layer, at least one prokinetic agent,comprising the steps of:(a) preparing the proton pump inhibitor in theform of enteric coating layered pellets; (b) mixing the enteric coatedpellets with pharmaceutically acceptable tablet excipients; (c) dryingthe mixture; (d) compressing the dry mixture into a multiple unit tabletwithout affecting any significant change of the acid resistance of theenteric coating layered pellets; and (e) spraying a coating layercomprising an aqueous suspension of the second component onto themultiple unit tableted dosage form; or (f) applying a separate layercomprising the second component in admixture with pharmaceuticallyacceptable excipients onto the multiple unit tablet dosage form.
 21. Amethod of treating disorders associated with gastro oesophageal refluxdiseases in mammals and man comprising administering to a host in needthereof a therapeutically effective dose of a multiple unit dosage formaccording to any one of claims 1, 2-6, 9-11, 12-17 or
 18. 22. The methodaccording to claim 21, wherein the disorder is a gastric disorderassociated with gastro oesophageal reflux diseases.